Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective

Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets.


Introduction
Carcinoma is the abnormal growth of normal cells that typically grow beyond their original boundaries, invade surrounding areas, spread to other organs, and result in metastasis, which is one of the main causes of cancer-related death, the second most common cause of deaths across the globe [1]. Around 10.0 million cancer-related fatalities (9.9 million excluding squamous cell carcinoma) and 19.3 million new cases of cancer (18.1 million excluding squamous cells carcinoma) were estimated globally by 2020. Up to 25% of cancer cases are caused by cancer-causing illnesses such as hepatitis as well as human papillomavirus infections. The most common malignancies in both genders are breast, lung, stomach, colorectal, thyroid, liver, and ovarian. The most fatal cancers are lung (1.8 million), liver (830,000), stomach (769,000), breast cancer (627,000), and colorectal (935,000). The most commonly diagnosed cancers worldwide are lung (2.2 million), breast (2.09 million), colorectal (1.9 million), prostate (1.28 million), skin (1.04 million), and stomach (1.04 million).
containing heterocyclic compounds are also widely present in synthetic drugs, e.g., azidothymidine, chlorpromazine, antipyrine, metronidazole, diazepam, captopril, isoniazid, chloroquinine, and barbituric acid [21]. Numerous active medicines and natural compounds contain heterocyclic scaffolds as their fundamental nuclei. According to statistics, ≥85% physiologically active molecules are heterocycles or contain one nitrogen atom in their intricate structures [22]. We searched ''Nitrogen containing heterocyclic compounds'' on ChEMBL (https://www.ebi.ac.uk/chembl/, accessed on 22 November 2022), an open access biological database, and found 2,331,700 compounds on 467 targets. With the help of ChEMBL, we plotted a graph between the molecular weight of nitrogen containing heterocyclic compounds with log P values and color, which indicated the violation of rule of 5 (RO5). LogP values of the reported molecules were directly correlated with their molecular weight ( Figure 1). As there are so many molecules violating RO5, to explore the correlation of RO5 with activity, we have plotted a heatmap of 929 nitrogen containing molecules violating RO5 against different biological targets, but certain molecules violating RO5 have biological activities (Figure 2). Drug development commonly employs Lipinski's rule of five. This criterion makes it possible to determine whether a bioactive molecule would likely possess the physical and chemical traits necessary for oral bioavailability. According to the Lipinski rule, certain physicochemical features determine how a medicine will behave in terms of absorption, distribution, metabolism, and excretion. The PChEMBL average value indicates the activity count for particular compounds [23].

Nitrogen-Containing FDA-Approved Anti-Cancer Drugs
There are many FDA approved drugs available on the market from natural as well as synthetic sources. Some of them with nitrogen atom are covered in Table 1 with their cellular target and year of approval.

Nitrogen-Containing FDA-Approved Anti-Cancer Drugs
There are many FDA approved drugs available on the market from natural as well as synthetic sources. Some of them with nitrogen atom are covered in Table 1 with their cellular target and year of approval.

Brigatinib
It inhibits the ability of the phosphate group to bind ALK and inhibits the activity of proteins STAT3, A.K.T., ERK1/2, and S6 both in vitro and in vivo.
Anaplastic lymphoma kinase (ALK) Inhibitor 2018 [26] 4. Entrectinib It interferes with the growth of cancer cells, which are eventually destroyed.
Anaplastic lymphoma kinase (ALK) Inhibitor 2019 [27] It prevents the multiplication of cancer cells by blocking the action of abnormal proteins.

Brigatinib
It inhibits the ability of the phosphate group to bind ALK and inhibits the activity of proteins STAT3, A.K.T., ERK1/2, and S6 both in vitro and in vivo.
Anaplastic lymphoma kinase (ALK) Inhibitor 2018 [26] 4. Entrectinib It interferes with the growth of cancer cells, which are eventually destroyed.
Anaplastic lymphoma kinase (ALK) Inhibitor 2019 [27] It inhibits the ability of the phosphate group to bind ALK and inhibits the activity of proteins STAT3, A.K.T., ERK1/2, and S6 both in vitro and in vivo.

Brigatinib
It inhibits the ability of the phosphate group to bind ALK and inhibits the activity of proteins STAT3, A.K.T., ERK1/2, and S6 both in vitro and in vivo.
Anaplastic lymphoma kinase (ALK) Inhibitor 2018 [26] 4. Entrectinib It interferes with the growth of cancer cells, which are eventually destroyed.
Anaplastic lymphoma kinase (ALK) Inhibitor 2019 [27] Inhibits will disrupt the ALK and ROS1mediated signaling, further inhibiting the growing tumor cells in ALK and ROS1 cells.

Brigatinib
It inhibits the ability of the phosphate group to bind ALK and inhibits the activity of proteins STAT3, A.K.T., ERK1/2, and S6 both in vitro and in vivo.
Anaplastic lymphoma kinase (ALK) Inhibitor 2018 [26] 4. Entrectinib It interferes with the growth of cancer cells, which are eventually destroyed.
Anaplastic lymphoma kinase (ALK) Inhibitor 2019 [27] It interferes with the growth of cancer cells, which are eventually destroyed.

Midostaurin
It Prevents the multiplication of cancer cells by blocking the action of abnormal proteins.
Fms-like tyrosine kinase (FLT3) inhibitor 2018 [30] 7. Quizartinib It inhibits cancer cell proliferation which leads to the death of the cells.

Midostaurin
It Prevents the multiplication of cancer cells by blocking the action of abnormal proteins.
Fms-like tyrosine kinase (FLT3) inhibitor 2018 [30] 7. Quizartinib It inhibits cancer cell proliferation which leads to the death of the cells.

Midostaurin
It Prevents the multiplication of cancer cells by blocking the action of abnormal proteins.
Fms-like tyrosine kinase (FLT3) inhibitor 2018 [30] 7. Quizartinib It inhibits cancer cell proliferation which leads to the death of the cells.

Midostaurin
It Prevents the multiplication of cancer cells by blocking the action of abnormal proteins.
Fms-like tyrosine kinase (FLT3) inhibitor 2018 [30] 7. Quizartinib It inhibits cancer cell proliferation which leads to the death of the cells.
Fms-like tyrosine kinase (FLT3) inhibitor 2018 [31] 8. Pexidarinib Inhibits the colony-stimulating factor (CSF1)/CSF1 receptor pathway Fms-like tyrosine kinase (FLT3) inhibitor 2019 [32] 9. Osimertinib mesylate The abnormal protein's ability to cause cancer cells to grow is blocked, which may also help tumors get smaller and slow down the spread of cancer cells.
Epidermal growth factor (EGF) receptor inhibitors 2015 [34] 11. Neratinib maleate The autophosphorylation is prevented on tyrosine residues receptor, and the Oncogenic signaling was reduced through mitogen-activated protein kinase and Akt pathways.
Epidermal growth factor (EGF) receptor inhibitors 2018 [36] The abnormal protein's ability to cause cancer cells to grow is blocked, which may also help tumors get smaller and slow down the spread of cancer cells.
Osimertinib mesylate The abnormal protein's ability to cause cancer cells to grow is blocked, which may also help tumors get smaller and slow down the spread of cancer cells.
Epidermal growth factor (EGF) receptor inhibitors 2015 [34] 11. Neratinib maleate The autophosphorylation is prevented on tyrosine residues receptor, and the Oncogenic signaling was reduced through mitogen-activated protein kinase and Akt pathways.
Epidermal growth factor (EGF) receptor inhibitors 2018 [36] Restricting the mutant form of E.G.F.R. causes the death of E.G.F.R. expressing tumor cells.
Osimertinib mesylate The abnormal protein's ability to cause cancer cells to grow is blocked, which may also help tumors get smaller and slow down the spread of cancer cells.
Epidermal growth factor (EGF) receptor inhibitors 2015 [34] 11. Neratinib maleate The autophosphorylation is prevented on tyrosine residues receptor, and the Oncogenic signaling was reduced through mitogen-activated protein kinase and Akt pathways.
Epidermal growth factor (EGF) receptor inhibitors 2018 [36] The autophosphorylation is prevented on tyrosine residues receptor, and the Oncogenic signaling was reduced through mitogen-activated protein kinase and Akt pathways.
Osimertinib mesylate The abnormal protein's ability to cause cancer cells to grow is blocked, which may also help tumors get smaller and slow down the spread of cancer cells.
Epidermal growth factor (EGF) receptor inhibitors 2015 [34] 11. Neratinib maleate The autophosphorylation is prevented on tyrosine residues receptor, and the Oncogenic signaling was reduced through mitogen-activated protein kinase and Akt pathways.

Duvelisib
Inhibit isoform gamma, essential for cytokine signaling and the pro-inflammatory response, and inhibit the isoform delta of PI3K(phospho-inositide3-kinase), which is Phosphatidylinositol 3-hydroxy kinase inhibitors 2018 [50] Inhibit isoform gamma, essential for cytokine signaling and the pro-inflammatory response, and inhibit the isoform delta of PI3K(phosphoinositide3-kinase), which is required for cell proliferation and survival.

Cytarabine
It prevents cancer cells from generating and repairing the D.N.A., which they require to thrive and proliferate.

Gefitinib
It prevents a variety of tyrosine kinases linked to transmembrane cell surface receptors from becoming phosphorylated intracellularly, including those linked to the epidermal growth factor receptor (EGFR-TK).

Abemaciclib
The action of an abnormal protein is blocked, which causes the cancer cell's signals to multiply Blocks the activity of CDK4 and CDK6 proteins (CDK4/6) 2017 [70,71] It prevents a variety of tyrosine kinases linked to transmembrane cell surface receptors from becoming phosphorylated intracellularly, including those linked to the epidermal growth factor receptor (EGFR-TK).

Lapatinib
It works by competitively binding to the intracellular ATP-binding site of the receptor, inhibiting the tyrosine kinase domains of the human epidermal growth factor receptor (HER)-2 and the epidermal growth factor receptor.
HER2 and E.G.F.R. antagonist 2007 [103] 58. Larotrectinib The activity of T.R.K. proteins is disrupted, which is caused by fusion in a family of genes known as N.T.R.K.

Lapatinib
It works by competitively binding to the intracellular ATP-binding site of the receptor, inhibiting the tyrosine kinase domains of the human epidermal growth factor receptor (HER)-2 and the epidermal growth factor receptor.
HER2 and E.G.F.R. antagonist 2007 [103] 58. Larotrectinib The activity of T.R.K. proteins is disrupted, which is caused by fusion in a family of genes known as N.T.R.K.

T.R.K. (Tropomyosin Receptor Kinase) inhibitor
2018 [104,105] It works by competitively binding to the intracellular ATP-binding site of the receptor, inhibiting the tyrosine kinase domains of the human epidermal growth factor receptor (HER)-2 and the epidermal growth factor receptor.

Erlotinib
The intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (E.G.F.R.) is inhibited Inhibition of epidermal growth factor receptor (E.G.F.R.)

Ibrutinib
It inhibits Btk's enzyme activity by forming a covalent bond with a cysteine residue (CYS-481) at the active site.

Lapatinib
It works by competitively binding to the intracellular ATP-binding site of the receptor, inhibiting the tyrosine kinase domains of the human epidermal growth factor receptor (HER)-2 and the epidermal growth factor receptor.
HER2 and E.G.F.R. antagonist 2007 [103] 58. Larotrectinib The activity of T.R.K. proteins is disrupted, which is caused by fusion in a family of genes known as N.T.R.K.

T.R.K. (Tropomyosin Receptor Kinase) inhibitor
2018 [104,105] The activity of T.R.K. proteins is disrupted, which is caused by fusion in a family of genes known as N.T.R.K.

Pyrimidine Derivatives as Anticancer Agents
Pyrimidines gained popularity in the history of organic chemistry as "m-Diazine" which is the product of uric acid catabolism. Brugnatelli discovered the first pyrimidine derivative, alloxan, in 1818 while oxidising uric acid with nitric acid. The heterocyclic six membered aromatic ring of pyrimidine contains nitrogen atoms in 1st and 3rd position. The melting and boiling temperatures of pyrimidine are 22.5 • C and 124 • C, respectively [113,114].
Fathalla et al. (2012) synthesized 10 pyrimidine derivatives and evaluated their antitumor activity against a liver cancer (HepG2) cell line by a comparison with the wellknown anticancer drugs 5-Flurouracil and Doxorubicin. While comparing the synthesized compounds, growth inhibition effectiveness was shown on the tested tumor cell line at doses between 1 and 10 µg/mL. The most potent compound in this study was found to be compound 1 with the IC 50 value of 3.56 µg/mL, whereas doxorubicin and 5-flurouracil were having IC 50 values 3.56 µg/mL and 5 µg/mL, respectively [115].  synthesized and evaluated the anti-tumor activity of 16 nitrogen heterocyclic compounds bearing a pyrimidine moiety. The newly developed pyrimidine derivatives were tested for in vitro anti-proliferative activity against human liver (HepG2), breast (MCF7), and normal fibroblast (WI-38) cell lines, and their efficacy was compared to Doxorubicin. Among all the tested compounds, compound 2 showed excellent anticancer activity with IC 50 values of 7.36, 10.76, and 6.7 µM respectively, whereas IC 50 values of doxorubicin were 4.5, 4.1, and 6.7 µM (WI-38) respectively [116]. Gupta et al. (2022) studied the anticancer activity of spiroisoquinoline-pyrimidine derivatives against the MCF-7 cancer cell line. Out of these, compound 3 having an ethoxy group from the acetylene molecule was found to be the most potent cytotoxic agent with an IC 50 value of 98.8 µM as compared to the reference Doxorubicin. An MTT assay was carried out at the concentration of 50 µM and it showed 60% of cell viability with control doxorubicin having 100% cell viability [117]. Al-Issa (2013) synthesized fused pyrimidines and tested them in vitro anti-tumour activity against human cancer cell line HEPG2. Out of these compounds, the most potent anticancer activity was shown by the compound 4 with the IC 50 value of 17.4 µg/mL as compared to the standard drug doxorubicin having an IC 50 value 1.2 µg/mL [118]. Osmania et al. (2022) synthesized a new pyrimidine-triazole derivatives and carried out studies on its anticancer effect. A total of 10 novel Pyrimidine-Triazole derivatives were synthesized in this study and they were evaluated against three cancer cell lines; A549, MCF-7, and NIH3T3. IC 50 values were calculated at 24 h and 48 h (incubation time). Two compounds, namely compound 5a and 5b, were found to be potent anticancer agents. Compounds 5a and 5b have the IC 50 [125].
All the reported pyrimidine derivatives (Figure 3 (1-11)) were acting as anticancer agents. The most potent compound among them was compound 10, having the lowest IC 50 value of 0.23 µM against MCF-7 cell line. It has a hydrazine moiety joined by phenyl amino linkage and pyrimidine with benzothiophene nucleus which may be responsible for its excellent activity.

Quinoline Derivatives as Anticancer Agents
Quinoline is a nitrogen containing heterocyclic aromatic compound, also known as 1-aza-napthalene or benzopyridine. Its molecular weight is 129.16 and molecular formula is C 9 H 7 N. The log P value is 2.04 while the pKb and pKa values are 4.85 and 9.5, respectively. Quinoline is a weak tertiary base and with acids it can produce salt and exhibits reactions akin to those of pyridine and benzene. Numerous naturally occurring chemicals (Cinchona Alkaloids) and pharmacologically active molecules with a wide range of biological activities include the quinoline nucleus in their structure. Diverse pharmacological activities (anticonvulsant, analgesic, cardiotonic, antibacterial, antifungal, anti-inflammatory, and anti-malarial) of quinoline have been reported [126]. . Compound 12 had sub-micromolar anti-proliferative activity in cancer cell lines that express Bcl-2, as well as a sub-micromolar IC 50 value in an ELISA experiment using the Bcl2-Bim peptide [127]. Mathada et al. (2022) studied the anticancer effect of quinoline and its derivatives. Hence, 62 compounds were synthesized in this study. Out of these, the most potent compound was found to be compound 13, which showed a potent anticancer effect against three cell lines, MDA-MB-231, HeLa, and SMMC-7721 with IC 50 values of 0.12, 0.08, and 0.34 µM respectively. Etoposide was used as standard drug with IC 50 values of 5.26, 2.98, and 3.48 µM respectively. Compound 13 had a unique capacity to induce apoptosis in HeLa cells, halt the cell cycle at the G0/G1 phase, elevate intracellular ROS (Reactive Oxygen Species) levels, and decrease mitochondrial membrane potential. Additionally, it had the ability to significantly reduce MEK1 kinase activity and disrupt the Ras/Raf/MEK/ERK transduction pathway [128].

Quinoline Derivatives as Anticancer Agents
Quinoline is a nitrogen containing heterocyclic aromatic compound, also known as 1-aza-napthalene or benzopyridine. Its molecular weight is 129.16 and molecular formula is C9H7N. The log P value is 2.04 while the pKb and pKa values are 4.85 and 9.5, respectively. Quinoline is a weak tertiary base and with acids it can produce salt and exhibits This also demonstrated the ability to cause apoptosis in HeLa cells.

Carbazole Derivatives as Anticancer Agents
A polycyclic aromatic hydrocarbon called carbazole has a broad aromatic system and a central nitrogen atom that exhibits substantial electron delocalization. It consists of a five-membered nitrogen-containing ring sandwiched between two six-membered benzene rings. It has an indole-like structure, but at the indole position 2-3, a second benzene ring is fused to the five-membered ring. When creating electron donor-electron acceptor (D-A) chemical dyes, carbazole is frequently used as a conjugated bridge [137]. Murali et al. (2017) studied the creation of hetero annulated isoxazolo-, pyrido-, and pyrimido carbazoles, also screening them for in vitro anticancer activity. By cyclo condensation with the appropriate reactants (hydroxylamine hydrochloride, malononitrile, and guanidine nitrate), the newly synthesized heterocycles isoxazolo-, pyrido-, and pyrimidocarbazoles were produced from the readily available 2-(3 -bromo-4 -methoxybenzylidene)-2,3,4,9-tetrahydro-1H-carbazol. All the synthesized substances were tested for in vitro cytotoxicity against the A-549 and MCF-7 human cancer cell lines. Compound 22 demonstrated substantial activity against MCF-7 with the IC 50 value of 20 µM as compared to cisplatin IC 50 value of 18 µM. All other compounds showed moderate to powerful activity and consequent apoptotic cell death, which was demonstrated by AO/EB and DAPI of fluorescence microscopy analysis [138]. Wang

Carbazole Derivatives as Anticancer Agents
A polycyclic aromatic hydrocarbon called carbazole has a broad aromatic system and a central nitrogen atom that exhibits substantial electron delocalization. It consists of a five-membered nitrogen-containing ring sandwiched between two six-membered ben-

Pyridine Derivatives as Anti-Cancer Agents
Pyridine has the chemical formula C 5 H 5 N and is a fundamental heterocyclic organic molecule. The word "pyridine" is taken from Greek and combines the words "idine" and "pyr," which both refer to aromatic bases. Picoline, the first pyridine base, was discovered by Anderson in 1846. It took quite some time for Wilhelm Korner and James Dewar to discover its structure. It resembles the well-known and fundamental aromatic molecule benzene in many ways, but with one C-H group replaced by an atom of Nitrogen. Like benzene, pyridine possesses a conjugated system of six delocalized electrons distributed around the heterocyclic ring. The molecule satisfies the Huckel requirements for aromaticity and is planar in nature [147]. Gomha

Pyridine Derivatives as Anti-Cancer Agents
Pyridine has the chemical formula C5H5N and is a fundamental heterocyclic organic molecule. The word "pyridine" is taken from Greek and combines the words "idine" and "pyr," which both refer to aromatic bases. Picoline, the first pyridine base, was discovered by Anderson in 1846. It took quite some time for Wilhelm Korner and James Dewar to discover its structure. It resembles the well-known and fundamental aromatic molecule benzene in many ways, but with one C-H group replaced by an atom of Nitrogen. Like benzene, pyridine possesses a conjugated system of six delocalized electrons distributed around the heterocyclic ring. The molecule satisfies the Huckel requirements for aromaticity and is planar in nature [147]. Gomha [157]. Ivasechko (2022) synthesized novel pyridine-thiazole hybrid molecules as potential anti-cancer agents and evaluated their anti-cancer activity against several kinds of tumors, e.g., carcinomas of the breast, lung, colon, glioblastoma, and leukemia. Two compounds showed the highest anti-cancer activity. The most potent compound reported was compound 42, with an IC 50 value of 2.79 µM against the MCF-7 cell line. Doxorubicin was standard with an IC 50 value of 1.04 µM against the MCF-7 cell line [158].
Among the above-reported potent anti-cancer compounds ( Figure 6 (32-42)) having a pyridine moiety, the most active compound which showed the best cytotoxic activity was compound 40a (a diaryl compound joined by pyridine ring. Diaryl rings were substituted with methoxy group on different positions). It showed the lowest IC 50 value of 0.0031 µM, 0.089 µM, and 0.0038 µM against the three human cancer cell lines MDA-MB-23, A549, and HeLa, respectively.

Imidazole Derivatives as Anticancer Agents
Heinrich Debus synthesized the first Imidazole in 1858 by reacting glyoxal and formaldehyde in the presence of ammonia. Derivatives of Imidazole are now widely used in many treatments and have recently attracted much attention. Various medicinal

Benzimidazole Derivatives as Anticancer Agents
Benzimidazole consists of benzene fused to the 4,5-positions of the imidazole ring. It is known as benzimidazole or benzoglyoxaline. The resonance in benzimidazole demonstrates its amphoteric nature and indicates that an electrophilic attack will occur either at N-1 or in the benzene ring [172]. Various studies have revealed that substituted benzimidazoles and heterocycles can easily interact with biopolymers, having pharmacological activity with lower toxicities. Because of the fused nitrogen nuclei, benzimidazoles are structural isosteres of nucleobases and readily interact with biomolecular targets, eliciting a wide range of biological activities, such as anti-inflammatory, antiulcer, anti-hypertensive, anthelmintic [173], and anticancer properties. For example, nocodazole, benzimidazole containing antineoplastic drug works by depolymerizing microtubules to achieve its effects [174]. Shao [171]. The above-reported anticancer compounds (Figure 7 (43-54)) have an imidazole moiety, which showed the best cytotoxic activity against representative cell lines. Furthermore, compound 49 showed the lowest IC50 value of 0.47 µM against epidermal growth factor receptor, whereas the control drug, gefitinib, had an IC50 value of 0.45 µM. Compound 49 had a quinazoline ring which was substituted with substituted aromatic ring joined by amino linkage.

Benzimidazole Derivatives as Anticancer Agents
Benzimidazole consists of benzene fused to the 4,5-positions of the imidazole ring. It is known as benzimidazole or benzoglyoxaline. The resonance in benzimidazole demonstrates its amphoteric nature and indicates that an electrophilic attack will occur either at N-1 or in the benzene ring [172]. Various studies have revealed that substituted benzimidazoles and heterocycles can easily interact with biopolymers, having pharmacological activity with lower toxicities. Because of the fused nitrogen nuclei, benzimidazoles are  [186]. The above-reported anticancer compounds (Figure 8 (55-66)) had a benzimidazole moiety, which showed the best cytotoxic activity against representative cell lines. Furthermore, compound 59 (having the quinazoline ring and a substituted aromatic ring) showed the lowest IC 50 value of 0.02 µM against VEGFR-2 with the control drug gefitinib.

Triazole Derivatives as Anticancer Agents
Triazole has been used in pharmaceuticals, agrochemicals, artificial materials, artificial acceptors, supramolecular ligands, and biomimetic catalysts. Heterocyclics have received particular attention due to their diverse pharmacological activities. The triazole ring is an essential five-membered heterocycle with three nitrogen atoms [187]. When creating new drug molecules, the triazole ring is a crucial isostere of imidazole, oxazole, pyrazole, and thiazole moieties. Many triazole-based derivatives have been extensively prepared and investigated for biological activities, which is one of the most active areas in new drug research and development [188]. Kurumurthy

Triazole Derivatives as Anticancer Agents
Triazole has been used in pharmaceuticals, agrochemicals, artificial materials, artificial acceptors, supramolecular ligands, and biomimetic catalysts. Heterocyclics have received particular attention due to their diverse pharmacological activities. The triazole ring is an essential five-membered heterocycle with three nitrogen atoms [187]. When creating new drug molecules, the triazole ring is a crucial isostere of imidazole, oxazole, pyrazole, and thiazole moieties. Many triazole-based derivatives have been extensively prepared and investigated for biological activities, which is one of the most active areas in  61, 9.12, 8.43, and 1.43 µM, respectively [198].
Above reported triazole compounds (Figure 9 (67-76)) showed the best cytotoxic activity against representative cell lines among their own series. Furthermore, compound 68 (having nitro substituted aromatic ring and imidazole ring joint by ethylene bride with sulphur linkage) showed the lowest IC 50 value, 0.38 µM, against MCF-7 cell lines as compared to standard drug, doxorubicin, having IC 50 0.65 µM.

β-Lactam Derivatives as Anticancer Agents
"β-lactams" represent the most well-known class of antibiotics. Since the 1920s, various new penicillin compounds have been developed, along with related beta-lactam families, including cephalosporins, cephamycins, monobactams, and carbapenems. Every new class of beta-lactam has been created to either deal with particular resistance mechanisms that have emerged in the targeted bacterial population or to broaden the spectrum of activity to encompass more bacterial species. Bacterial enzymes, which hydrolyze the beta-lactam ring and leave the drug inert, represent the main cause of resistance to betalactams [199]. Banik et al. (2003) synthesized beta-lactam-based heterocyclic derivatives and evaluated their anti-neoplastic activity on nine representative cell lines. All the synthesized compounds showed good anticancer activity when tested on BRO, MCF-7, MDA-231, OV-CAR, SKOV, PC-3, HL-60, K-562, and HT-29 cell lines. Among them, compound 77 showed potent activity at IC 50 [200].

β-Lactam Derivatives as Anticancer Agents
"β-lactams" represent the most well-known class of antibiotics. Since the 1920s, various new penicillin compounds have been developed, along with related beta-lactam families, including cephalosporins, cephamycins, monobactams, and carbapenems. Every new class of beta-lactam has been created to either deal with particular resistance mechanisms that have emerged in the targeted bacterial population or to broaden the spectrum  [209]. In summary, the above reported beta-lactam derivatives (Figure 10 (77-86)) were acting as anticancer agents. The most potent compound among them was compound 86 with 3-hydroxy-4-methoxyphenyl-1-3,4,5-trimethoxyphenyl terminal moiety, having the lowest IC 50 value of 0.017 µM against MCF-7 (breast cancer) cell line.

Indole Derivatives as Anticancer Ahents
Benzene and pyrrole rings are fused to form the heterocyclic molecule known as indole. A.V. Baeyer and C.A. Knop identified the compound, indole, as the fundamental component of the naturally occurring dye indigo. Indole was detected in coal tar by R. Weissgerber in 1910. It has an m.p. between 52 and 54 • C and a b.p. of 254.7 • C. It is an opaque solid. It is readily soluble in most solvents, including benzene, diethyl ether, and ethanol. Additionally, it is volatile in steam, barely soluble in cold water, and miscible in hot water. Since indole comes from a natural source and is a component of orange blossom oil and jasmine oil, it is found in many perfumes, has been used for a long time to mask unpleasant odors, and has crucial role in the synthesis of the amino acid, tryptophan [210]. Analyzing the above reported indole-based derivatives ( Figure 11 (87-97)) discussed herewith, all compounds act as anticancer agents. The most potent compound among them was the compound 88, which was modified to change the indole substituents, the indole-2-carboxamide/carbohydrazide moiety, and substitute the aromatic ring for improved anticancer efficacy against colon cancer cell line (COLO 205) at the lowest GI 50 value, 0.018 µM.

Pyrazole Derivatives as Anticancer Agents
The chemical formula for pyrazole is C 3 H 4 N 2 and it has a five-membered ring structure with three C and two nitrogen atoms nearby. It's conjugate acid's pKa at 25 • C is 2.49, making it a weak base with a pKb of 11.5 (pKa). Ludwig Knorr introduced the word pyrazole in 1883. They are categorized as alkaloids because of their chemical nature and distinct pharmacological effects. The first naturally occurring pyrazole was 1-pyrazolyl-alanine, discovered in 1959 from watermelon seeds. Pyrazoles are reported to have a variety of biological activities, including neuroprotective, anti-fungal, antitubercular, anti-inflammatory, anti-convulsant, anticancer, anti-viral, ACE inhibitory, antiviral, cholecystokinin-1 receptor antagonist, and estrogen receptor (ER) agonistic activity [222].

Pyrazole Derivatives as Anticancer Agents
The chemical formula for pyrazole is C3H4N2 and it has a five-membered ring structure with three C and two nitrogen atoms nearby. It's conjugate acid's pKa at 25 °C is 2.49, making it a weak base with a pKb of 11.5 (pKa). Ludwig Knorr introduced the word pyrazole in 1883. They are categorized as alkaloids because of their chemical nature and distinct pharmacological effects. The first naturally occurring pyrazole was 1-pyrazolyl-alanine, discovered in 1959 from watermelon seeds. Pyrazoles are reported to have a variety of biological activities, including neuroprotective, anti-fungal, antitubercular, anti-inflammatory, anti-convulsant, anticancer, anti-viral, ACE inhibitory, antiviral, cholecystokinin-1 receptor antagonist, and estrogen receptor (ER) agonistic activity [222].
Abdelgawad et al. (2018) designed and synthesized pyrazole-based heterocyclic derivatives and evaluated their antineoplastic activity on two representative cell lines. All  [232].
Analyzing the above reported pyrazole-based heterocyclic derivatives ( Figure 12  (98-107)) discussed herewith, all compounds act as anticancer agents. The most potent compound among them was compound 104 with thioxodihydropyrimidine-4,6(1H,5H)dione terminal moiety and two substituted aromatic rings, having the lowest IC 50 value 0.028 µM against HepG2 cell lines. Authors found that these substances downregulated CDK1 expression in HepG2 cells and cell cycle arrest during the G2/M phase. ated their anticancer activity on five representative cell lines. All the synthesized com-pounds showed good anti-proliferative activity against A549, MCF-7, HepG-2, Caco-2, and PC3 cell lines. Among them, compound 106 showed potent activity with IC50 values 18.85, 23.43, 23.08, 23.08, and 18.50 µM, respectively. Among the tested cell lines, compound 106 showed the most potent activity against HepG-2 cell lines with the IC50 value 23.08 µM. 5-FU was used as standard with IC50 values 83.03, 93.79, 96.89, 112.24, and 82.26 µM, respectively [231]. Bakhotmah et al. (2020) designed and synthesized pyrazole-based heterocyclic derivatives and evaluated their anticancer activity on three representative cell lines. All the synthesized compounds showed potent anticancer activity against HCT-116, Hep-G2, and MCF-7 cell lines. Among them, compound 107 showed very good activity with IC50 values 4.13, 5.29, and 6.79 µM respectively. Among the tested cell lines, compound 107 showed the most potent activity against HCT-116 cell lines with the IC50 value 4.13 µM. Doxorubicin was used as control drug with IC50 values 0.493, 0.467, and 0.469 µM, respectively [232].
Analyzing the above reported pyrazole-based heterocyclic derivatives ( Figure 12  (98-107)) discussed herewith, all compounds act as anticancer agents. The most potent compound among them was compound 104 with thioxodihydropyrimidine-4,6(1H,5H)dione terminal moiety and two substituted aromatic rings, having the lowest IC50 value 0.028 µM against HepG2 cell lines. Authors found that these substances downregulated CDK1 expression in HepG2 cells and cell cycle arrest during the G2/M phase.

Quinazoline Derivatives as Anticancer Agents
The parent compound of quinazoline is naphthalene, a mancude organic heterobicyclic compound in which the carbon atoms at positions 1 and 3 have been substituted with nitrogen atoms. It is an azaarene and has an ortho-fused heteroarene. Quinazoline and

Quinazoline Derivatives as Anticancer Agents
The parent compound of quinazoline is naphthalene, a mancude organic heterobicyclic compound in which the carbon atoms at positions 1 and 3 have been substituted with nitrogen atoms. It is an azaarene and has an ortho-fused heteroarene. Quinazoline and quinazolin-none scaffolds constitute a sizeable class of physiologically active nitrogen heterocyclic compounds. Numerous anticancer drugs are marketed based on these moieties, including gefitinib, erlotinib, lapatinib, afatinib, and vandetanib [233]. Ghorab

Quinoxaline Derivatives as Anticancer Agents
The nitrogen-containing heterocyclic molecule quinoxalines, commonly known as benzopyrazines, has a ring complex composed of a pyrazine ring and a benzene ring [245]. The majority of quinoxaline derivatives are produced synthetically. In quinoxaline, two benzene rings combine, expanding the variety of resonance structures available to these systems. It possesses a zero-dipole moment [246]. Due to the wide range of pharmacological activities that quinoxalines exhibit, they have received a lot of interest. It is regarded as a crucial moiety for anticancer medications. Since the 1980s, when certain quinoxalinone derivatives were produced and investigated for their cytotoxic activity, the screening of quinoxaline as an anticancer scaffold has continued [247]. Ismail et al. (2010) synthesized a set of quinoxaline 1,4-di-oxides which were tested for their anticancer activities against the U251 (brain tumors) and Hepg2 (liver carcinoma). Among the synthesized compounds, 119 and 120 showed maximum activity against Hepg2 cell lines with IC 50 values of 0.77 and 0.50 µg/mL, respectively. Tirapazamine was used as standard and its IC 50 value against HepG2 was 56.6 µg/mL. For carbamate and acid azide derivatives to be cytotoxic, the 7-methoxy (electron-donating group) was important. The activity was decreased when quinoxaline 1,4-dioxide was converted to quinoxaline 4-oxide [248].

Quinoxaline Derivatives as Anticancer Agents
The nitrogen-containing heterocyclic molecule quinoxalines, commonly known as benzopyrazines, has a ring complex composed of a pyrazine ring and a benzene ring [245]. The majority of quinoxaline derivatives are produced synthetically. In quinoxaline, two benzene rings combine, expanding the variety of resonance structures available to these  [255]. Analyzing the above reported quinoxaline-based heterocyclic derivatives (Figure 14 (119-143)), all compounds act as anticancer agents. The most potent compound among them was compound 122 in which the quinoxaline ring was substituted at N-1 atom by acetohydrazide moiety and bromine, having the IC 50 value of 0.01 µg/mL against MCF-7 cell line.

Isatin Derivatives as Anticancer Agents
Isatin is an endogenous substance found in animals that has a number of pharmacological features, such as anticancer action [256]. In the present era of medicine, there are many challenges that affect human health, especially when it comes to tumors. As a result, new treatments that target tumor cells specifically will inevitably need to be introduced to the armory for treating these malignancies [257]. Aziz et al. (2017) prepared a few sets of isatin-based benzoazine heterocyclic rings, such as isatin-quinoxaline, quinazoline, and phthalazines hybrids. They used three human cancer cell lines, i.e., HT-29, ZR-75, and A-549, for testing the cytotoxicity of all the synthesized compounds. A majority of the synthesized molecules showed potent cytotoxic activity. Sunitinib was used as standard drug with an average IC 50 value of 8.11 µM. Among synthesized compounds, 144 showed maximum anticancer activity with average IC 50 value of 5.53 µM [258].  [255]. Analyzing the above reported quinoxaline-based heterocyclic derivatives ( Figure 14 (119-143)), all compounds act as anticancer agents. The most potent compound among them was compound 122 in which the quinoxaline ring was substituted at N-1 atom by acetohydrazide moiety and bromine, having the IC50 value of 0.01 µg/mL against MCF-7 cell line.

Isatin Derivatives as Anticancer Agents
Isatin is an endogenous substance found in animals that has a number of pharmacological features, such as anticancer action [256]. In the present era of medicine, there are many challenges that affect human health, especially when it comes to tumors. As a result, new treatments that target tumor cells specifically will inevitably need to be introduced to the armory for treating these malignancies [257]. Aziz et al. (2017) prepared a few sets of isatin-based benzoazine heterocyclic rings, such as isatin-quinoxaline, quinazoline, and phthalazines hybrids. They used three human cancer cell lines, i.e., HT-29, ZR-75, and A-549, for testing the cytotoxicity of all the synthesized compounds. A majority of the synthesized molecules showed potent cytotoxic activity. Sunitinib was used as standard drug with an average IC50 value of 8.11 µM. Among synthesized compounds, 144 showed maximum anticancer activity with average IC50 value of 5.53 µM [258].  All the above reported isatin-based heterocyclic derivatives (Figure 15 (144-150)) were observed to act as anticancer agents. The most potent compound among them was compound 145 with the EC 50 value of 0.1 µM against the BxPC-3 cell line, which contained diazole with 2-naphthyl group and 4-CH 3 substituent ring for optimal antiproliferative activity. 549 (lung) cell lines. A majority of the prepared compounds show potent cytotoxicity. The most active compound was 147 with IC50 values of 0.74, 0.76, and 2.02 µM against ZR-75, A-549, and HT-29 respectively. Sunitinib was used as standard drug with IC50 values of 10.14, 8.31, and 5.87 µM for HT-29, ZR-75, and A-549, respectively [261]. Panga et al. (2016) synthesized isatin-benzoic acid derivatives and evaluated them in vitro for anticancer activity against HeLa and MCF-7 cell lines. The synthesized compounds showed good anticancer activity towards both the cells. Compound 148 showed the highest activity towards both cell lines having IC50 values of 9.28 and 14.89 µM and Vinblastine was used as positive control here with IC50 values of 4.02 and 7.14 µM, respectively [262]. Eldehna et al. (2021) synthesized isatin-thiazolo benzimidazole derivatives and evaluated their cytotoxic activity against MDA-MB-231 and MCF-7 breast cancer cell lines by using sulforhodamine B colorimetric (SRB) assay. The compound 149 shows good anticancer activity with IC50 values of 6.50 and 2.02 µM against MDA-MB-231 and MCF-7 cell lines, respectively. Compound 150 with IC50 values of 2.60 and 3.01 µM respectively shows better anticancer activity than standard drug staurosporine, having IC50 values of 4.29 and 3.81 µM, respectively [257].
All the above reported isatin-based heterocyclic derivatives (Figure 15 (144-150)) were observed to act as anticancer agents. The most potent compound among them was compound 145 with the EC50 value of 0.1 µM against the BxPC-3 cell line, which contained diazole with 2-naphthyl group and 4-CH3 substituent ring for optimal antiproliferative activity.

Pyrrolo-benzodiazepines Derivatives as Anticancer Agents
Many actinomycetes species naturally produce or contain pyrrolo-benzodiazepines (PBD) derivatives. PBD binds covalently to DNA, inhibiting transcription factors and DNA replication, thus slowing cellular growth [263]. Bose et al. (2012) synthesized pyrrole-benzodiazepine derivatives and evaluated the cytotoxic activities of the synthesized compounds against HL-60 (human promyelocytic leukemia), THP-1 (human acute mon-

Pyrrolo-Benzodiazepines Derivatives as Anticancer Agents
Many actinomycetes species naturally produce or contain pyrrolo-benzodiazepines (PBD) derivatives. PBD binds covalently to DNA, inhibiting transcription factors and DNA replication, thus slowing cellular growth [263]. Bose  Many actinomycetes species naturally produce or contain pyrrolo-benzodiaz (PBD) derivatives. PBD binds covalently to DNA, inhibiting transcription facto DNA replication, thus slowing cellular growth [263]. Bose et al. (2012) synthesize role-benzodiazepine derivatives and evaluated the cytotoxic activities of the synth compounds against HL-60 (human promyelocytic leukemia), THP-1 (human acut ocytic leukemia), U-937 (human histiocytic lymphoma), A-549 (lung carcinoma Jurkat (Human T-cell leukemia) cell lines. The most active compound was 151 wi values of 0.49, 4.13, 3.44, and 6.58 µM against THP-1, HL-60, U-937, and Jurkat cel THP-1, U-937, HL-60, and Jurkat leukemia cell lines were all cultivated in RPM while A-549 was grown in Dulbecco's Modified Eagle Medium (DMEM). Etoposid as reference drug had IC50 values 2.16, 17.94, 1.83, and 5.35 µM against THP-1, U-93 60, and Jurkat cells [264]. Kamal et al. (2012) synthesized pyrrolo-benzodiazepine conjugated with ben dolone derivatives. The synthesized compounds were evaluated for antiproliferat tivity in human cancer cell lines of the prostrate, skin, lung, colon, and by using th assay. A majority of the synthesized derivatives showed good anticancer activity pound 152 showed maximum activity with IC50 values of 1.21, 1.72, 1.05, and 1. against Colo-205, A431, A549, and PC-3, respectively. Doxorubicin was used as th tive control and had IC50 values of 1.69, 0.03, 1.02, and 2.51 µM [265]. Chen et al. synthesized the new series of pyrrolo-benzodiazepine-triazole derivatives and the cancer activity was evaluated on A375 cells. Most of the synthesized derivatives s potent cytotoxic activity. On A375 cells, compound 153 showed a greater inhibitory with the IC50 value of 2.2 µM [266]. All the above reported Pyrrolo-benzodiazepines heterocyclic derivatives (Figure 16 (151-153)) discussed herewith were observed to anticancer agents. The most potent compound among them was compound 151 w IC50 value of 0.49 µM against THP-1, containing a fluorine analogue which may role in cell-permeability, which was generally enhanced by fluoro compounds.

Pyrido[2,3-d] Pyrimidine Derivatives as Anticancer Agents
Purines, quinazolines, pteridines, and pyrido-pyrimidines are examples of b nitrogen-containing heterocyclic compounds that are well-known pharmacophores dicinal chemistry. Examples of commercial medications with a bicyclic main str
All the Pyrido[2,3-d]pyrimidine based heterocyclic derivatives (Figure 17 (154-165)) discussed herewith were observed to act as anticancer agents. The most potent compound among them is compound 163 with GI 50 of 0.02 µM against PANC-1, due to the presence of an ethyl group at the C-2 position and substituted aromatic ring with fluorine group. ues of 10.52 and 3.02 µM. Ribociclib was used as positive control with IC50 values 24.35 and 4.81 µM, respectively [276].
All the Pyrido[2,3-d]pyrimidine based heterocyclic derivatives (Figure 17 (154-165)) discussed herewith were observed to act as anticancer agents. The most potent compound among them is compound 163 with GI50 of 0.02 µM against PANC-1, due to the presence of an ethyl group at the C-2 position and substituted aromatic ring with fluorine group.

Conclusions
Heterocyclic systems have earned their place as true pillars of medicinal chemistry owing to their innate ingenuity, adaptability, and outstanding physicochemical potencies. The majority of natural products and pharmaceuticals that are currently prescribed contain the primary heterocyclic systems. Nitrogen heterocycles stand out among them because about 60% of the FDA-approved pharmaceuticals are nitrogen-based heterocycles. The current study deduced that chemically synthesized nitrogen-containing heterocycles (pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines) are important and versatile molecules against the different forms

Conclusions
Heterocyclic systems have earned their place as true pillars of medicinal chemistry owing to their innate ingenuity, adaptability, and outstanding physicochemical potencies. The majority of natural products and pharmaceuticals that are currently prescribed contain the primary heterocyclic systems. Nitrogen heterocycles stand out among them because about 60% of the FDA-approved pharmaceuticals are nitrogen-based heterocycles. The current study deduced that chemically synthesized nitrogen-containing heterocycles (pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3d]pyrimidines) are important and versatile molecules against the different forms of cancer. The spectrum of nitrogen-based molecules used in medicine is expanding every day and their numerous analogues offer a promising and significant route for the discovery of medications with a variety of biological applications.
The compiled studies confirm the potential of nitrogen heterocyclic molecules in cancer treatment. The reported promising compounds from every scaffold present excellent activity against the different cell lines and kinase inhibitory assay which could be used in the structural based design of efficacious nitrogen-based anticancer drugs.  Data Availability Statement: All the data given in this manuscript has been taken from published research articles, given in the list of references and are available online.

Acknowledgments:
The authors are thankful to Central University of Punjab and DST-FIST, India and South Ural State University, Russia for providing infrastructural facilities for the successful completion of this study.

Conflicts of Interest:
The authors declare no conflict of interest.